Method for preparing acylated products

ABSTRACT

Acylation of nitrogen containing compounds utilizing esters as acylation agents in the presence of salts of substituted pyridine compounds.

United States Patent Fujimoto et al,

[ Feb. 18, 1975 METHOD FOR PREPARING ACYLATED PRODUCTS Inventors: Yasuo Fujimoto; Nobuhiro Nakamizo, both of Tokyo, Japan Assignee: Kyowa Hakim Kogyo Co., Ltd,

Tokyo, Japan Filed: June 25, 1970 Appl. No; 49,918

Foreign Application Priority Data June 30, 1969 Japan 44-51061 References Cited OTHER PUBLICATIONS Groggins, P H.; Unit Processes in Organic Synthesis (i958) pub. by McGraw-Hill (N.Y.) Q0262.G7c.8. p. 410 cited.

Primary ExaminerLorraine A. Weinberger Assistant Examiner-L. A. Thaxton Attorney, Agent, or FirmFitzpatrick, Cella, Harper & Scinto [57] ABSTRACT Acylation of nitrogen containing compounds utilizing esters as acylation agents in the presence of salts of substituted pyridine compounds.

4 Claims, N0 Drawings METHOD FOR PREPARING ACYLATED PRODUCTS This invention relates to acylation reactions of nitrogen-containing compounds utilizing esters as acylation agents. More specifically, this invention relates to a method for preparing compounds having a group by reacting a carboxylic acid ester, carbonic acid ester, carbamic acid ester or sulfur-analogs thereof with a nitrogen-containing compound having at least one hydrogen on said nitrogen atom in the presence of a novel catalyst. The preferred novel catalysts are metal salts or quaternary ammonium salts of a compound containing a pyridine nucleus directly substituted by a hydroxyl or mercapto group.

The use of halides or anhydrides of carboxylic acids in acylating nitrogen compounds such as amines is well known in the art. Furthermore, esters of carboxylic acids have sometimes been used as acylating agents but generally have a low reactivity and are, therefore, not practical in most cases. Recently, in peptide synthesis reactions, the so-called active esters, for example, pnitrophenyl ester or polyhalogenated phenyl esters, have been widely utilized. The reactivities of these active esters are considerably greater than those of the ordinary alkyl esters. However, their reaction rates sometimes are low and, therefore, various catalysts for these reactions have been investigated. See, for example, R. Schwyzer, M. Feurer, B. Iselin: Helv. Chim. Acta, Vol. 38, page 83 (1955), H. C. Beyerman, W. Maassen Van den Brink: Proc. Chem. Soc., page 266 (1963), and Nakamizo: Bull. Chem. Soc. Japan, Vol. 42, pages 1,071 and 1,078 (1969). Such alkyl esters as the methyl ester, etc. are cheaper than acid halides, acid anhydrides, active esters, etc., and it would be very advantageous if they could practically be used in acylatron.

The present inventors have found that derivatives containing anions of a compound having a pyridine skeleton whose nucleus bears an hydroxyl or mercapto substituent serve as particularly effective catalysts for acylation reactions of nitrogen compounds by esters, including the so-called active esters. As counterpart cations for these anions, various metal ions and the quaternary ammonium ion are utilized. The preferred metal ions include the alkali metals, for example, lithiurn, sodium and potassium and the alkali earth metals, for example, calcium. The preferred ammonium ion is a tetra substituted ion wherein the substituents are lower alkyl, for example, ethyl.

Furthermore, the pyridine nucleus can have substituent groups other than the hydroxyl and mercapto groups. Such additional substituent groups include the following; lower alkyl groups containing from 1 to 6 carbon atoms, for example, methyl, ethyl, tert-butyl and the like; aryl groups, for example, phenyl and tolyl; aralkyl groups, for example, benzyl; lower alkoxy groups, for example, methoxyl and ethoxyl; nitro groups; cyano groups and the like. It is also possible for more than one substituent to be present. Furthermore, the substituent can take the form of fused ring structures containing the pyridine nucleus together with other cyclic structures, for example, quinoline or isoquinoline.

These novel catalysts have not been heretofore described in the literature and have an enormously high catalytic activity, as compared with previously known catalysts such as acetic acid, 2-hydroxypyridine, and 1,2,4-triazole. In view of the diversity of industrially applicable ranges of the acylation reactions of nitrogen compounds, these values are very great. For example, when the preparation of the t-butyl ester of benzyloxycarbonyl-L-phenylalanylglycine from the p-nitrophenyl ester of benzoxycarbonyl-L-phenylalanine and tbutylester of glycine is carried out at 30C. in anhydrous dioxane, the catalytic rate constant of acetic acid is about 50 (l. /mol. 'min.) and that of 2-hydroxypyridine is about 40 (l. /mol. 'min.), whereas the catalytic rate constant of, for example, the sodium salt of Z-hydrQxy-pyridine is about 20,000 l /mol. -min.). As the catalysts of the present invention show such a high catalytic activity, the reaction time can be considerably shortened in the present invention as compared to the conventional method. Sometimes, it is even possible to effect reactions which could not be carried out by conventional methods.

The nitrogen-containing compounds useful in the present invention are amines with at least one hydrogen atom attached to the nitrogen atom, i.e., primary and secondary amines including the following: alkylamincs, for example, methylamine; arylamines, for example. benzylamine and aniline; substituted arylamincs, for example, nitroaniline; heterocyclic amines, for example, piperidine, hydrazines and substituted hydrazines, for example, phenylhydrazine; amides and substituted amides, and urea and substituted ureas, for example, thiourea. Other suitable nitrogen-containing compounds include hydroxylamine and substituted hydroxylamines, amino acids, peptides and the like.

The esters useful in the present invention are composed of specific acid and alcohol portions. The acid portions are preferably derived from aroyl acids, alkanoyl acids, carbonic acids, amino acids, carbamic acids and the like. The alcohol portions of the esters are derived from lower alkyl, aryl and substituted aryl alcohols and the like. Sulfur analogs of these esters are also useful in the present invention.

The method of the present invention is widely applicable to the production of various carboxylic acid amides and imides including peptides, polyamides, hydrazides, hydroxamic acides, N-acylamidines, N- acylguanidines, urea derivatives, urethan derivatives, nitrogen-containing heterocyclic compounds containing an amide bond, and the like.

Now, the present invention is explained, referring to several examples, but the applicable range of the present invention is not restricted thereto.

EXAMPLE 1 Snythesis of methyl ester of benzyloxycarbonyLL- valyl-L-valine:

'---) Z-L-Val-Val-OMe KOO-N0 wherein Z represents a benxyloxycarbonyl group; Val a valine residual group; Me a methyl group) Valine methyl ester prepared from 1.7 g. of valine methyl ester hydrochloride is dissolved in 50 ml. of ethyl acetate, and 0.12 g. of the sodium salt of 2-hydroxypyridine is added thereto. Then, 3.7 g. of benzyloxycarbonyl-L- valine-p-nitrophenylester is added at room temperature, whereupon the reaction immediately starts. The reaction solution changes to yellow due to the formation of p-nitrophenol. As determined by thin layer chromatography, the reaction is almost complete in minutes. Then, the reaction solution is washed once with 30 ml. of water, 5 times with 30 ml. of an aqueous 1N sodium carbonate solution, twice with 30 ml. of 1N hydrochloric acid, and finally three times with 50 ml. of water in succession, and the organic layer is dried with anhydrous sodium sulfate. After the sodium sulfate has been filtered off, the filtrate is concentrated under reduced pressure, and the residual oily matter is crystallized from ethyl acetate-petroleum benzin (1:3). Yield 85 percent.

Elemental analysis:

C H N Calculated (C H N O 62.62 7.74 7.69 Found 62.83 7.69 7.45

When a sodium salt of 6-n-amyl-2-hydroxypyridine,

5-cyano-2-hydroxypyridine, 2hydroxy4- methoxypyridine, 2-hydroxy-6-phenylpyridine, 2-hydroxy-6-phenethylpyridine or 1- EXAMPLE 2 Synthesis of benXyloxycarbonyl-L-phenylalanine pnitroanilide:

2.8 g. of p-nitroaniline and 2.66 g. of the potassium salt of 2'hydroxypyridine are dissolved in 50 ml. ofdimethylacetamide. Benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester in the amount of 8.4 g. is added thereto, and the solution is allowed to stand at room temperature. After hours, 200 ml. of an aqueous 1N sodium carbonate solution is added thereto, and the solution is stirred for one hour to hydrolyze the unreacted ester. The resulting solution is extracted with 200 ml. of ethyl acetate. The organic layer is washed 6 times with 50 ml. of an aqueous 1N sodium carbonate solution, 4 times with 50 ml. of IN hydrochloric acid, and

3 times with 70 ml. of water. After having been dried I with sodium sulfate, the organic layer is concentrated. 6.1 g. of benzyloxycarbonyl-L-phenylalanine pnitroanilide is obtained, when recrystalized from chloroform-ether. yield: 73 percent, m.p. 21 1C.

Elemental analysis:

C H N Calculated (C ;,H ,N, O,,) 65.86 5.05 10.02 Found 66.07 5.43 10.19

When the potassium salt of 4-hydroxypyridine is used, the desired product is obtained in yield of 52 percent. No reation takes place at all without the catalyst.

EXAMPLE 3 Synthesis of benzyloxycarbonyl-L-valine benzylamide:

1.1 ml. of benzylamine is dissolved in 200 ml. of dichloromethane, and 0.13 g. of the sodium salt of 2- mercaptopyridine is suspended therein. Then, 5.0 g. of benzyloxy carbonyl-L-valine pentaehlorophenyl ester is added thereto. As determined by thin layer chromatography, the period required to consume one-half of the reactants is about 10 minutes. After three hours, treatment is effected in the same manner as in the previous example, and the dichloromethane layer is concentrated, whereby 3.1 g. of crude crystals are obtained (yield: 91 percent). By recrystallization from ethyl acetate, 2.7 g. of needle-like crystals are obtained. m.p. l74.5 C.

1 When there is no catalyst present, the time required to consume one-half of the reactants is about one day.

EXAMPLE 4 Synthesis of N-benzylacetamide:

2.1 g. of benzylamine, 7.4 g. of methyl acetate and 1.5 g. of the sodium salt of 4,6-dimethyl-2- hydroxypyridine are dissolved in 30 ml. of dimethyl acetamide and heated at about 78C. for 4.5 hours. As determined by thin layer chromatography, all but a trace of the benzylamine is consumed. 200 ml. of water and 0.9 ml. of concentrated hydrochloric acid are added to the reaction solution, and the solution is extracted three times with ml. of ethyl acetate. The organic layer is washed with 100 ml. of water, and. after drying with sodium sulfate, concentrated and crystallized. Recrystallization from 300 ml. of etherpetroleum benzin (1:1), 2.5 g. of needle-like crystals of N-benzyl aeetamide are obtained (yield: 84 percent). m.p. 60.5 62C.

When no catalyst is employed, large amounts of unreacted benzylamine are recovered and only a very small amount of the desired product is formed.

EXAMPLE 5 in 2 hours. The product is worked up as previously de scribed to give an oil which is crystallized from acetone-water. 18.7 g. of N-(benzyloxycarbonylglycyl)- piperidine are obtained (yield: 68 percent). m.p. 111 112C. A single spot is obtained therefrom by thin layer chromatography. An additional 5.9 g. of crystals are obtained from the mother liquor, (yield: 21 percent). m.p. 1095' 112C.

Elemental analysis (first crop):

C H N Calculated (c 5HgoNgog) 65.19 7.30 10.14 Found 65.12 7.50 10.06

EXAMPLE 6 Synthesis of 4-amino-6-hydroxy-2- mercaptopyrimidine:

0.57 g. of ethyl cyanoacetate and 0.38 g. of thiourea are heated under reflux in 3 ml. of methanol in the presence of 1.17 g. of the sodium salt of 2- hydroxypyridine. After completion of reaction, 4 ml. of water is added, and the solution is neutralized with 0.58 ml. of acetic acid, to deposit the desired monohydrate crystals are obtained. Yield: 82 percent. The ultraviolet absorption spectrum agrees closely with the literature values.

When urea, guanidine or acetamidine is used in place of the thiourea, the correspondingly substituted pyrimidine is produced.

None of the desired product is produced in this reaction when the sodium salt of 2-hydroxypyridine is omitted or is replaced by an equimolar amount of triethylamine.

EXAMPLE 7 Synthesis of N-benzoyl-N-phenylhydrazine:

2.16 g. of phenylhydrazine and 3.22 g. of benzoic acid cyanomethyl ester are heated at 50C. for one hour in 10 ml. of ethanol in the presence of 1.14 g. of the calcium salt of 2-hydroxypyridine, whereby N-benzoyl-N '-phenylhydrazine are obtained in yield of 88 percent, mp. 170C.

When the reaction is carried out without the catalyst under the same conditions, the yield is only 23 percent.

EXAMPLE 8 Synthesis of palmitohydroxamic acid:

14.2 g. of ethyl palmitate and 2 g. of hydroxylamine are reacted at room temperature in 300 ml. of ethanol in the presence of 1.7 g. of the sodium salt of 2- hydroxyquinoline. The reaction is complete in 5 hours, and 11.7 g. of palmitohydroxamic acid are obtained (yield: percent), m.p. 101C. after recrystallization from ethanol-petroleum ether( 1:1).

lfthe catalyst is omitted, a reaction time of about two days is required.

EXAMPLE 9 Synthesis of t-butyloxycarbonyl-L-proline:

l 1.5 g. of L-proline is dissolved in 4N sodium hydroxide, and 100 ml. of dimethyl formamide, 50 ml. of chloroform, 10.1 g. of the lithium salt of Z-hydroxypyridine and 36.6 g. of t-butylpentachlorophenyl carbonate are added thereto. The solution is stirred at room temperature for three hours, after which 100 ml. ofchloroform and 200 ml. of water are added. After shaking, the water layer is acidified to a pH of 2 with 1N hydrochloric acid, and extracted with 200 ml. of ethyl acetate. The product is worked up as previously described to give t-butyloxycarbonyl-L-proline in 79 percent yield, mp. 137C.

When triethylamine is used in place of the lithium salt of 2-hydroxypyridine, it requires about 20 hours to obtain the same amount of product.

EXAMPLE 10.

Synthesis of N-methyl-N-phenyl urea:

15.1 g. of phenyl N-methylcarbamate, 9.3 g. of ani line and 5.4 g. of the tetraethylammonium salt of 2-hydroxy-5-nitro-pyridine are refluxed in 200 ml. of ethanol for 5 hours. The reaction solution is concentrated, and the residue is dissolved in 100 ml. of chloroform, washed successively with 50 m1. of 1N sodium carbonate, 50 ml. of 1N hydrochloric acid and 100 ml. of water, and dried. By concentrating to dryness and recrystallizing from ml. of ethanol, crystals of N- methyl-N-phenylurea having a m.p. of 151C. are obtained in 91 percent yield.

When phenyl N-methyldithiocarbamate is used in place of phenyl N-methylcarbamate, N-methyl-N'- phenylthiourea is obtained in 79 percent yield, m.p. 113 C. In either case, the reaction rate is considerably lower without the catalyst than with the catalyst.

What is claimed is:

1. In the process for preparing a carboxylic acid amide wherein a primary or secondary amine selected from alkylamines, arylamines and substituted arylamines is acylated with an ester derived from aliphatic or aromatic carboxylic acid, the improvement which comprises carrying out said acylation in the presence of an alkali-metal salt, an alkaline earth metal salt of a quaternary ammonium salt of a compound containing a pyridine nucleus directly substituted by a hydroxy group, a mercapto group, or a group selected from alkyl groups having 1 to 6 carbon atoms, aryl groups, aralkyl groups, alkoxy groups having 1 to 6 carbon atoms, nitro groups, and cyano groups.

2. The process of claim 1 wherein the compound containing the pyridine nucleus is a quinoline or an isoquinoline.

3. The process of claim 1 wherein the carboxylic acid amide is benzyloxycarbonyl-L-valinebenzylamide.

4. The process of claim 1 wherein the salt is the sodium salt of 2-hydroxy pyridine. 

1. IN THE PROCESS FOR PREPARING A CARBOXYLIC ACID AMIDE WHEREIN A PRIMARY OR SECONDARY AMINE SELECTED FROM ALKYLAMINES, ARYLAMINES AND SUBSTITUTED ARYLAMINES IS ACYLATED WITH AN ESTER DERIVED FROM ALIPHATIC OR AROMATIC CARBOXYLIC ACID, THE IMPROVEMENT WHICH COMPRISES CARRYING OUT SAID ACYLATION IN THE PRESENCE OF AN ALKALI-METAL SALT, AN ALKALINE EARTH METAL SALT OF A QUATERNARY AMMONIUM SALT OF A COMPOUND CONTAINING A PYRIDINE NUCLEUS DIRECTLY SUBSTITUTED BY A HYDROXY GROUP, A MERCAPTO GROUP, OR A GROUP SELECTED FROM ALKYL GROUPS HAVING 1 TO 6 CARBON ATOMS, NITRO GROUPS, AND CYANO GROUPS HAVING 1 TO 6 CARBON ATOMS, NITRO GROUPS, AND CYANO GROUPS.
 2. The process of claim 1 wherein the compound containing the pyridine nucleus is a quinoline or an isoquinoline.
 3. The process of claim 1 wherein the carboxylic acid amide is benzyloxycarbonyl-L-valinebenzylamide.
 4. The process of claim 1 wherein the salt is the sodium salt of 2-hydroxy pyridine. 